We propose a functional genomics investigation of differential immune system and growth hormone responses, using a novel comparative population approach with a natural human model. The cultural transition to agriculture that began ~12,000 years ago precipitated a major shift in the burden of human endemic infectious diseases. The vast majority of modern humans now live in agriculture-based societies, with an evolutionary history shaped in part by these relatively recent infectious disease profile changes. Most genetic association studies of disease - or of the related functional genomic response to disease - that have been conducted to date have focused exclusively on agriculture-based populations. Yet direct comparisons between agriculturalist and hunter-gatherer populations would provide important, novel insights into how evolutionary responses to the agricultural transition have influenced human physiology. This is true for both the modern human disease response and other biological traits that differ between agriculturalists and hunter-gatherers, such as body size. In the proposed study we will investigate the differential immune system and growth hormone responses between an agriculturalist and hunter-gatherer population using a powerful in vitro system in which the cells of 50-89 individuals from each population will be challenged with growth hormones and ligands that mimic viral and bacterial infections, followed by RNA-seq to identify genome-wide population differences in the regulatory responses. These results will then be compared to genome-wide SNP genotype and targeted resequencing data to identify and characterize genetic loci with potential functional and evolutionary significance for inter- population immune response and body size differences. These integrated analyses will contribute to our understanding of human growth and development functional genomic pathways and also shed light on how the human immune system has been affected by the cultural transition to agriculture, thereby advancing our understanding of the modern human disease response and medical outcomes.